Section

Darier’s Disease

Darier’s disease is a genodermatosis of autosomal dominant inheritance causing abnormalities of keratinization stemming from defects in calcium regulation in keratinocytes.

The classic skin manifestation is an eruption of hyperkeratotic papules, typically in a seborrheic distribution. Characteristic nail and mucous membrane involvement is common.

Superinfection of the skin lesions of Darier’s may result in clinical flares; important additional exacerbating factors include heat, humidity, UV light, perspiration, stress, and medications. Treatment should be adjusted accordingly and vigilant monitoring for superinfection is critical.

Introduction

Darier’s disease is a genodermatosis of autosomal dominant inheritance causing abnormalities of keratinization. The gene mutation associated with Darier’s is the ATP2A2 gene encoding SERCA-2, a calcium ATPase pump of the endoplasmic reticulum; the resulting disruption in calcium homeostasis in keratinocytes results in poor cell-cell adhesion with subsequent dyskeratosis affecting skin, nails, and mucous membranes. The hallmark skin lesion is a hyperkeratotic papule. The diagnosis of Darier’s disease is thus dependent on clinical features, family history and a characteristic histopathology.

Individuals affected by Darier’s disease typically develop manifestations of the disease in the first or second decade of life, not at birth. The classic eruption consists of hyperkeratotic, verrucous papules, classically in a seborrheic distribution: scalp, forehead, central face including the nasolabial folds, retroauricular neck, upper trunk, groin, and intergluteal cleft. Involvement of intertriginous sites can result in vegetative plaques. Other clinical variants include a cornifying variant, characterized by hypertrophic, vegetative lesions, primarily on the lower extremities, and localized forms in dermatomal, blaschkoid, or linear distribution, suggestive of somatic mosaicism. Some patients may have both variants simultaneously. The classic nail findings include V-shaped nicking, red and white streaking, or longitudinal ridging. Oral lesions, present in 13-50% of patients, include white umbilicated papules found on the palate, gingiva, and buccal mucosa (in order of frequency), sometimes coalescing into plaques with characteristic cobblestoned pattern.

The skin lesions of Darier’s are exacerbated by seasonal variation, especially by heat, humidity, UVB light; additional triggers include mechanical trauma, systemic lithium medication, and other chemical exposures. Superinfection by staphylococcal or streptococcal bacteria, or by herpes virus, can result in widespread flaring of the disease. Because the underlying genetic defect cannot yet be corrected, therapeutic strategies attempt to minimize the clinical consequences of abnormal keratinization and to treat the complications that result from the inherited defect. Systemic and topical retinoids are the mainstay. Because of seasonal exacerbations and partial remissions, therapy should be adjusted accordingly, and vigilant monitoring for superinfection with culture-directed antibiotic treatment as needed is critical. Because cutaneous squamous cell carcinoma is a rare complication of Darier’s disease, ongoing monitoring for malignancy is also required.

The currently accepted primary treatment of moderate-to-severe Darier’s disease is systemic retinoids. Isotretinoin and acitretin are equally effective for most patients. Acitretin may be more effective for the hyperkeratotic lesions. For either medication, the starting dose is 0.2-0.3 mg/kg/day, with gradual escalation of the dose to the therapeutic range of 0.5-1 mg/kg/day. Successful use of alitretinoin in Darier’s disease has recently been reported.

Topical tretinoin 0.025% gel or 0.1% cream before bed may suffice for patients with mild or limited disease. Adapalene or tazarotene are acceptable alternative topical retinoids in mild clinical disease. Some patients may tolerate or respond better to one agent over another, so do not abandon topical treatment until all three topical retinoid medications have been tried.

Flares of Darier’s disease are often precipitated by secondary bacterial (most common), herpetic superinfection, and candidal infections owing both to a defective skin barrier and to minor immunologic dysfunction in this disease. Hence, therapy often includes an initial 10- to 14-day course of a bacteriocidal antibiotic (e.g., oral cephalexin 500 mg three times daily, dicloxacillin 500 mg three times daily) directed against coagulase-positive S. aureus, the most commonly encountered pathogen. This should be combined with rifampin 600 mg once daily for at least one week.

Because Darier’s disease flares after acute exposure to sunlight (UVB is the active wavelength), instruct patients to use maximum photoprotection with sun protective clothing and a high UVB SPF sunblock (SPF 30 or greater) daily.

Heat, sweating, and friction can exacerbate Darier’s disease either directly or indirectly via secondary bacterial infections. Weight reduction and even surgical removal of pendulous skin folds or breasts may be associated with dramatic improvement in macerated areas.

Patients with a history of frequent bacterial superinfections may benefit from prophylactic bleach baths (1/4 cup in a full household bathtub, soak for 10-15 minutes once or twice weekly) to disease-prone areas.

Subsequent steps

As soon as a good response to systemic retinoids is observed (i.e., usually after about 4-8 weeks), reduce the daily retinoid dose. Maintenance therapy constitutes the lowest dose that suppresses the most severe disease features. Since the disease tends to be relatively quiescent during winter months, if possible discontinue retinoid therapy completely during this period, thereby potentially minimizing long-term side effects.

Pitfalls

Some patients with the seborrheic variant of Darier’s disease may be worsened by systemic retinoids owing to the tendency of these agents to cause epidermal fragility.

Frequent courses of oral antibiotics often result in colonization by resistant strains of staphylococci.

As described above, secondary infections owing to heat and excessive friction, as well as to acute exposure to ultraviolet light, can cause disease flares.

Systemic retinoids can cause both acute and chronic side effects. Hence, patients must be fully aware of the risks and benefits of this therapy. It is imperative that female patients utilize consistent contraception to avoid pregnancy during retinoid treatment.

When to refer to a dermatologist

When the diagnosis is not clear.

To start systemic retinoids, or when systemic retinoids are not effective.

For treatment-resistant disease, additional treatment modalities may be considered.

For screening for cutaneous malignancy that may arise in association with the disease.

Clinical Case

Case 1

32-year-old male

Presents with worsening Darier’s disease

No significant past medical history except for known diagnosis of Darier’s. The patient was intermittently on oral isotretinoin, which controlled his disease during times of skin flare. He currently takes no medications except for use of topical retinoid creams as needed to minimize the hyperkeratotic lesions on the neck, upper chest

Strong family history of Darier’s disease

Review of systems is notable only for recent fevers in association with worsening rash

Presents for management of increasing erythema, crusting on the retroauricular neck, trunk, and flexural areas

Initial evaluation

Healthy-appearing male

Low-grade fever is noted

Widespread hyperkeratotic papules on the scalp, ears, neck, chest, axillae with notable crusting and increased erythema since last clinical evaluation

Diagnosis: favor Darier’s disease with staphylococcal superinfection

Skin cultures (bacterial, candidal, and herpes simplex viral culture) are obtained. The patient is empirically started on doxycycline 100 mg b.i.d. for 10 days

Follow-up in 1 week

One-week follow-up evaluation

The skin cultures confirmed a diagnosis of superinfection with methicillin-resistant Staphylococcus aureus. No candida or viral infection was found

The patient reports dramatic improvement of his skin erythema and crusting

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